Dosenovic Pia, Ádori Monika, Adams William C, Pedersen Gabriel K, Soldemo Martina, Beutler Bruce, Karlsson Hedestam Gunilla B
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
Department of Genetics, Center for Genetics of Host Defense, UT Southwestern Medical Center, Dallas, TX, USA.
Immunol Cell Biol. 2015 Feb;93(2):136-46. doi: 10.1038/icb.2014.82. Epub 2014 Oct 14.
Signalling through Toll-like receptors (TLRs) by endogenous components of viruses or bacteria can promote antibody (Ab) isotype switching to IgG2a/c. Multiple cell types are capable of responding to TLR stimulation in vivo and the processes underlying TLR-induced Ab isotype switching are not fully defined. Here, we used feeble mice, which are deficient in the peptide/histidine transporter solute carrier family 15 member 4 (Slc15a4), and fail to produce cytokines including interferon alpha (IFNα) in response to TLR9 stimulation, to study Ab isotype switching to IgG2c in response to vaccination. We demonstrate that the production of IgG2c in response to CpGA-adjuvanted vaccines was severely reduced in feeble mice, while a more subtle defect was observed for CpGB. The reduced IgG2c production in feeble could not be ascribed to defective plasmacytoid dendritic cell (pDC) responses alone as we found that splenic cDCs and B cells from feeble mice were also defective in response to TLR9 ligation ex vivo. We conclude that Slc15a4 is required for intact function of TLR9-expressing cells and for effective Ab isotype switching to IgG2c in response to CpG-adjuvanted vaccines.
病毒或细菌的内源性成分通过Toll样受体（TLR）发出信号，可促进抗体（Ab）亚型转换为IgG2a/c。多种细胞类型在体内能够对TLR刺激作出反应，而TLR诱导的Ab亚型转换的潜在机制尚未完全明确。在此，我们使用了虚弱小鼠，其肽/组氨酸转运体溶质载体家族15成员4（Slc15a4）存在缺陷，对TLR9刺激无反应，无法产生包括干扰素α（IFNα）在内的细胞因子，以研究接种疫苗后Ab亚型转换为IgG2c的情况。我们证明，在虚弱小鼠中，对含CpGA佐剂疫苗产生的IgG2c显著减少，而对CpGB则观察到更细微的缺陷。虚弱小鼠中IgG2c产生减少不能仅归因于浆细胞样树突状细胞（pDC）反应缺陷，因为我们发现，来自虚弱小鼠的脾cDC和B细胞在体外对TLR9连接也存在缺陷。我们得出结论，Slc15a4是表达TLR9的细胞完整功能以及对含CpG佐剂疫苗有效进行Ab亚型转换为IgG2c所必需的。
